Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in the Western World and is characterised by the accumulation of immuno-incompetent, monoclonal CD5+B-lymphocytes2. Some patients show rapid disease progression with a mean survival of less than 36 months, whereas others exhibit a more indolent disease profile with a better prognosis. Three important laboratory prognostic markers are used to stratify patient risk: somatic mutation of immunoglobulin variable heavy chain (VH) genes, the expression of CD38 and the expression of the T-cell tyrosine kinase, ZAP-701,3-10. There is evidence that different prognostic subsets of CLL cells have altered signalling properties that may contribute to disparity in clinical outcomes. Cells from CLL patients with mutated VH genes, who have a good clinical prognosis, often show a reduced response to IgM ligation of the B-cell receptor (BCR) as measured by changes in tyrosine phosphorylation11,12. In addition, the poor prognostic markers, CD38 and ZAP-70, have also been shown to correlate with the ability of CLL cells to signal via the BCR with high expression associated with signalling competence13,14. However, the interplay between the three prognostic markers and cell signalling is the subject of debate.
CLL cells with unmutated VH genes usually have higher ZAP-70 expression and, following anti-IgM ligation of the BCR, are able to activate NF-κB.6 Indeed, ZAP-70 appears to act as an enhancer of BCR signaling7. NF-κB proteins are transcription factors affecting many different survival signalling pathways and play an important role in the growth, differentiation and apoptosis of normal B-lymphocytes.8 In addition, NF-κB has been shown to be involved in the pathology of both non-haemopoietic and haemopoietic malignancies including CLL and non-Hodgkin's lymphoma.9 
NF-κB is a collective name for a group of inducible homo- and hetero-dimeric transcription factors made up of members of the Rel family of DNA binding proteins. In humans this family is comprised of c-Rel, Rel B, p50, p52 and p65 (Rel A) which when bound in the cytoplasm to inhibitory IκB proteins are inactive.10 Various factors including ligation of CD40 and the BCR result in proteasomal degradation of IκB releasing NF-κB which then translocates to the nucleus.8;10 Once in the nucleus NF-κB can enhance survival by inducing anti-apoptotic proteins including IAPs, FLICE (FADD-like IL-1β-converting enzyme) and FLIP (FADD-like interleukin 1β-converting enzyme-inhibitory protein).11-13 CLL cells have been reported to exhibit high constitutive NF-κB activation compared to normal B-lymphocytes.14-16 Whilst the exact causes of constitutive over expression of NF-κB are not fully resolved, many factors including Akt activation, BCR signalling, CD40 ligation, IL-4 and BAFF have been shown to increase NF-κB activity and enhance CLL cell survival with members of the Bcl-2 family being important transcriptional targets.6;17-20 
The crucial question for patients presenting with CLL is the nature of the disease progression. Clearly, patients with an aggressive form of the disease need to receive early clinical intervention. In contrast those patients with a more benign form of the disease simply need to be monitored until such time as the disease takes on a more aggressive form at which point chemotherapy can be commenced. As many will appreciate, it is inappropriate to expose someone presenting with a disease that is unlikely to be life-threatening for up to 30 years with highly dangerous chemotherapeutic drugs. An assay that is therefore able to discriminate between an aggressive form of CLL and a more benign form would be useful.